核导入受体 具有类域的RNA结合蛋白的逆异常相过渡
Lin Guo1, Hong Joo Kim2, Hejia Wang1
1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|April 21, 2018
概括
核进口受体 (NIR) 预防和逆转神经退行性疾病中的病态蛋白质聚合. 卡里奥菲林-β2特别针对具有子类域的RNA结合蛋白 (RBPs),恢复细胞功能并减轻疾病的进展.
科学领域:
- 神经生物学
- 分子生物学
- 生物化学
背景情况:
- 具有类域的RNA结合蛋白 (RBPs) 可以形成涉及神经退行性疾病的病理聚合物.
- 核RBP如TDP-43和FUS的错误定位和聚合是这些疾病的标志.
- 在PrLDs中的突变可以加速RBP纤维化和疾病发作.
研究的目的:
- 调查核进口受体 (NIR) 在与PrLD相辅导和分解RBP中的作用.
- 确定NIR是否可以逆转与疾病相关的RBP的病态阶段过渡和纤维形成.
- 评估NIR在神经退行性疾病中的治疗潜力.
主要方法:
- 在体外测试以评估Karyopherin-β2和Importin-α/Karyopherin-β1对RBP纤维化和水凝形成的影响.
- 对RBP阶段分离和分解的分析.
- 在模型生物体中进行体内研究,以评估Karyopherin-β2对RBP局部化,功能和神经退行的影响.
主要成果:
- 通过激活它们的核定位信号 (NLS),抑制和逆转FUS,TAF15,EWSR1,hnRNPA1和hnRNPA2的纤维化.
- 进口蛋白-α/ karyopherin-β1可以预防和逆转TDP-43纤维化.
- 卡里奥菲林-β2可以溶解由FUS和hnRNPA1形成的异相分离液体和水凝.
- 在体内,Karyopherin-β2防止RBP聚合,恢复核定位和功能,并拯救神经退行.
结论:
- 核导入受体,特别是Karyopherin-β2,作为与疾病相关的RBPs的强大分解剂.
- 通过防止异常的相位过渡和纤维状体的形成,NIR可以在治疗上恢复RBP的平衡.
- 针对NIR提供了一个有前途的治疗策略来缓解神经退行.
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